Integrated genome and transcriptome analyses reveal the mechanism of genome instability in ataxia with oculomotor apraxia 2

Abstract

Significance Ataxia with oculomotor apraxia (AOA) is a progressive neurodegenerative disease characterized by early‐onset autosomal recessive cerebellar ataxia with oculomotor apraxia, peripheral axonal neuropathy, and impaired motor functions. The AOA-2 subgroup results from mutations in an RNA/DNA helicase, Senataxin, which is encoded by the SETX gene. Here, we carried out integrated genome and transcriptome analyses of cell lines derived from individuals with AOA2, as well as CRISPR/Cas9 generated SETX knockouts, and observed genome-wide chromosome fragility. Genome instability was caused by increased transcription stress and the accumulation of RNA/DNA hybrids near gene promotors, resulting in aberrant DNA repair that led to changes in gene-expression profiles. The results indicate that SETX -defective cells exhibit transcription stress that leads to chromosome fragility.